Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Comparative Study
. 2005 Sep;77(3):389-407.
doi: 10.1086/444437. Epub 2005 Jul 26.

Susceptibility genes for age-related maculopathy on chromosome 10q26

Johanna Jakobsdottir  1 , Yvette P Conley, Daniel E Weeks, Tammy S Mah, Robert E Ferrell, Michael B Gorin
Affiliations
Comparative Study

Susceptibility genes for age-related maculopathy on chromosome 10q26

Johanna Jakobsdottir et al. Am J Hum Genet. 2005 Sep.

Abstract

On the basis of genomewide linkage studies of families affected with age-related maculopathy (ARM), we previously identified a significant linkage peak on 10q26, which has been independently replicated by several groups. We performed a focused SNP genotyping study of our families and an additional control cohort. We identified a strong association signal overlying three genes, PLEKHA1, LOC387715, and PRSS11. All nonsynonymous SNPs in this critical region were genotyped, yielding a highly significant association (P < .00001) between PLEKHA1/LOC387715 and ARM. Although it is difficult to determine statistically which of these two genes is most important, SNPs in PLEKHA1 are more likely to account for the linkage signal in this region than are SNPs in LOC387715; thus, this gene and its alleles are implicated as an important risk factor for ARM. We also found weaker evidence supporting the possible involvement of the GRK5/RGS10 locus in ARM. These associations appear to be independent of the association of ARM with the Y402H allele of complement factor H, which has previously been reported as a major susceptibility factor for ARM. The combination of our analyses strongly implicates PLEKHA1/LOC387715 as primarily responsible for the evidence of linkage of ARM to the 10q26 locus and as a major contributor to ARM susceptibility. The association of either a single or a double copy of the high-risk allele within the PLEKHA1/LOC387715 locus accounts for an odds ratio of 5.0 (95% confidence interval 3.2-7.9) for ARM and a population attributable risk as high as 57%.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Location of CIDR SNPs and locally genotyped SNPs with respect to candidate genes. Positions, distances, and nucleotide positions along chromosome 10 are derived from NCBI Entrez Gene and dSNP databases.
Figure 2
Figure 2
A, LD patterns in GRK5 (Block 1), RGS10 (SNP 6), PLEKHA1 (Block 2), LOC387715 (Block 3), and PRSS11 (Block 4). B, LD patterns in CFH (Block 1). Squares shaded pink or red indicate significant LD between SNP pairs (bright red indicates pairwise D′=1), white squares indicate no evidence of significant LD, and blue squares indicate pairwise D′=1 without statistical significance. Significant SNPs from the CCREL allele test are highlighted in green (see table 6). Three SNPs (rs6428352, rs12258692, and rs11538141) were not included, because of very low heterozygosity, and one SNP (rs2736911) was not included, because it was uninformative. Note that the blocks were drawn to show clearly the position of the genes and do not represent haplotype blocks.
Figure 3
Figure 3
Two-point (2pt) and multipoint (mpt) linkage results on chromosome 10. The panel on the left summarizes the results when all SNPs were used for analysis. The panel on the right summarizes the results when only htSNPs were used. The peaks marked “F” represent likely false peaks due to high SNP-SNP LD, whereas the peaks marked “G” and “P” correspond to the loci containing GRK5 and PLEKHA1, respectively. The horizontal lines indicate the 1-unit support interval of multipoint Sall (i.e., maximum Sall-1).
Figure 4
Figure 4
LD patterns on chromosome 10 based on analysis of 196 CIDR SNPs and 179 unrelated controls. A, The false peak at 135 cM (see fig. 3); the SNP with the largest Sall in the peak is highlighted in green. B, The false peak at 142 cM (see fig. 3); the SNP with the largest Sall in the peak is highlighted in green. C, Linkage peak. Significant SNPs, from CCREL (table 5), that overlie the five genes (GRK5, RGS10, PLEKHA1, LOC387715, and PRSS11) are highlighted in green. Squares shaded pink or red indicate significant LD between SNP pairs (bright red indicates pairwise D′=1), white squares indicate no evidence of significant LD, and blue squares indicate pairwise D′=1 without statistical significance. LD is measured using D′, and the values within the squares give pairwise LD in D′/100.
Figure 4
Figure 4
LD patterns on chromosome 10 based on analysis of 196 CIDR SNPs and 179 unrelated controls. A, The false peak at 135 cM (see fig. 3); the SNP with the largest Sall in the peak is highlighted in green. B, The false peak at 142 cM (see fig. 3); the SNP with the largest Sall in the peak is highlighted in green. C, Linkage peak. Significant SNPs, from CCREL (table 5), that overlie the five genes (GRK5, RGS10, PLEKHA1, LOC387715, and PRSS11) are highlighted in green. Squares shaded pink or red indicate significant LD between SNP pairs (bright red indicates pairwise D′=1), white squares indicate no evidence of significant LD, and blue squares indicate pairwise D′=1 without statistical significance. LD is measured using D′, and the values within the squares give pairwise LD in D′/100.
Figure 4
Figure 4
LD patterns on chromosome 10 based on analysis of 196 CIDR SNPs and 179 unrelated controls. A, The false peak at 135 cM (see fig. 3); the SNP with the largest Sall in the peak is highlighted in green. B, The false peak at 142 cM (see fig. 3); the SNP with the largest Sall in the peak is highlighted in green. C, Linkage peak. Significant SNPs, from CCREL (table 5), that overlie the five genes (GRK5, RGS10, PLEKHA1, LOC387715, and PRSS11) are highlighted in green. Squares shaded pink or red indicate significant LD between SNP pairs (bright red indicates pairwise D′=1), white squares indicate no evidence of significant LD, and blue squares indicate pairwise D′=1 without statistical significance. LD is measured using D′, and the values within the squares give pairwise LD in D′/100.
Figure 5
Figure 5
Multipoint linkage results for chromosome 1. The panel on the left summarizes results when all SNPs were used for analysis, and the panel on the right summarizes results when only htSNPs were used. The peaks marked “F” represent likely false peaks due to high SNP-SNP LD, whereas the peak marked “C” corresponds to the CFH gene. The horizontal lines indicate the 1-unit support interval of multipoint Sall (i.e., maximum Sall over CFH-1).
Figure 6
Figure 6
LD patterns on chromosome 1 based on analysis of 679 CIDR SNPs and 179 unrelated controls. A, The false peak at 188 cM (see fig. 5); the SNP with the largest Sall in the peak is highlighted in green. B, The false peak at 202 cM (see fig. 5); the SNP with the largest Sall in the peak is highlighted in green. C, Linkage peak. Significant SNPs, from CCREL (table 5), that overlie CFH are highlighted in green. Squares shaded pink or red indicate significant LD between SNP pairs (bright red indicates pairwise D′=1), white squares indicate no evidence of significant LD, and blue squares indicate pairwise D′=1 without statistical significance. LD is measured using D′, and the values within the squares give pairwise LD in D′/100.
Figure 6
Figure 6
LD patterns on chromosome 1 based on analysis of 679 CIDR SNPs and 179 unrelated controls. A, The false peak at 188 cM (see fig. 5); the SNP with the largest Sall in the peak is highlighted in green. B, The false peak at 202 cM (see fig. 5); the SNP with the largest Sall in the peak is highlighted in green. C, Linkage peak. Significant SNPs, from CCREL (table 5), that overlie CFH are highlighted in green. Squares shaded pink or red indicate significant LD between SNP pairs (bright red indicates pairwise D′=1), white squares indicate no evidence of significant LD, and blue squares indicate pairwise D′=1 without statistical significance. LD is measured using D′, and the values within the squares give pairwise LD in D′/100.
Figure 6
Figure 6
LD patterns on chromosome 1 based on analysis of 679 CIDR SNPs and 179 unrelated controls. A, The false peak at 188 cM (see fig. 5); the SNP with the largest Sall in the peak is highlighted in green. B, The false peak at 202 cM (see fig. 5); the SNP with the largest Sall in the peak is highlighted in green. C, Linkage peak. Significant SNPs, from CCREL (table 5), that overlie CFH are highlighted in green. Squares shaded pink or red indicate significant LD between SNP pairs (bright red indicates pairwise D′=1), white squares indicate no evidence of significant LD, and blue squares indicate pairwise D′=1 without statistical significance. LD is measured using D′, and the values within the squares give pairwise LD in D′/100.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

Web Resources

    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for ARMD-1, CFH, PLEKHA1, PRSS11, GRK5, and RGS10)
    1. Division of Statistical Genetics, http://watson.hgen.pitt.edu/ (for Mega2)
    1. The R Project for Statistical Computing, http://www.r-project.org/ (for R statistical software)

References

    1. Abecasis GR, Cherny SS, Cookson WO, Cardon LR (2002) Merlin—rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30:97–101 - PubMed
    1. Abecasis GR, Yashar BM, Zhao Y, Ghiasvand NM, Zareparsi S, Branham KE, Reddick AC, Trager EH, Yoshida S, Bahling J, Filippova E, Elner S, Johnson MW, Vine AK, Sieving PA, Jacobson SG, Richards JE, Swaroop A (2004) Age-related macular degeneration: a high-resolution genome scan for susceptibility loci in a population enriched for late-stage disease. Am J Hum Genet 74:482–494 - PMC - PubMed
    1. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265 - PubMed
    1. Browning SR, Briley JD, Briley LP, Chandra G, Charnecki JH, Ehm MG, Johansson KA, Jones BJ, Karter AJ, Yarnall DP, Wagner MJ (2005) Case-control single-marker and haplotypic association analysis of pedigree data. Genet Epidemiol 28:110–122 - PubMed
    1. Conley YP, Thalamuthu A, Jakobsdottir J, Weeks DE, Mah T, Ferrell RE, Gorin MB (2005) Candidate gene analysis suggests a role for fatty acid biosynthesis and regulation of the complement system in the etiology of age-related maculopathy. Hum Mol Genet 14:1991–2002 - PubMed

Publication types

Substances

-